Formaldehyde sulphoxylate derivatives of diphenyl-sulphides,-disulphides, -sulphoxides, and -sulphones, and methods of production



Patented Mar. 18, 1941 UNITED STATES I v 2,234,981 PATENT OFFICEFORMALDEHYDE SULPHOXYLATE DERIVA- TIVES OF DIPHENYL-SULPHIDES, -DISUL-PHIDES,

-SULPHOXIDES,

AND -SUL-' PHONES, AND METHODS OF PRODUCTION Sanford M. Rosenthal andHugo Bauer, Washington, D. 0., assignors to Government of the UnitedStates, as represented by the Secretary of the Treasury No Drawing.

Application January 27, 1938,

' Serial No. 187,216

28 Claims.

(Granted under the act of March a, 1883, as amended April 30, 1928; 3700. G. 757) was OzCiizlIhF-OIi-Q n in which R is a radical selected fromthe group consisting of S, S--S, SO, and SOaand R is a radical selectedfrom the group consisting of NH2, NH.CHzSO2Na, and N02; and in themethod of their preparation; The invention is particularly dbncernedwith compounds of 4-4'-diamino diphenylsulphoxide and 4-amino-4-nitrodiphenyl sulphoxide as well as the corresponding sul- 1311011635,,111which one or two amino groups are substituted by formaldehydesulphoxylate, and also contemplates, in its broader aspects, thecorresponding sulphides similarly substituted.

The new compounds described in the present invention are superior incertain respects to 4-4- diamino diphenylsulphoxide,4-4-a'mino-nitrodiphenylsulphoxide and the corresponding sulphones, andmay serve to replace them in medical applications. The products of theinvention are much less toxic and show a greater index of therapeuticefliciency than the original sulphoxides or sulphones cited above. Theproducts of this invention are intended to be administered by mouth orby injection.

(1) 4-4'-diamino diphenylsulphone was shown to possess curative actionagainst bacterial infections due to organisms such as the streptococcus,pneumococcus, meningococcus and. staphyiococcus (see Buttle,,Stephenson, Smith and Foster, Lancet, 1937, I, 1331) (2)4-amino-4'-nitro diphenylsulphone has been shown to possesschemotherapeutic action against bacterial infections by Fourneau,Trefouel, Nitti and Bovet (Bull. dc lAcademie de Medicine, 1937, 118,117), and also by Levaditi, Girard, Vaisman, Ray and Richard .(Compt.

Rend. de IAcademie de Medicine, 1937, 205, 1018).

(3) 4-4-diamino diphenyl sulphoxide and i) 4 amino 4 '-nitro-phenylsulphoxide were shown to possess curative action against bacterialinfections by Girard, Ray and Richard (see Nature, 1937, 140, 283), andby Levaditi, Girard, Vaisman, Ray and Richard (Compt. Rend. Acad. deSci, 1937, 205, 1018) We have shown that the formaldehyde sulphoxylatederivatives of the compoundsezil) (2) (3) and.

(4) render them water soluble so that they become suitable for injectionpurposes. The formaldehyde sulphoxylate derivatives also decrease thetoxicity of these compounds and result in a higher index of therapeuticefiiciency upon bacterial infections.

The general method of preparing these compounds is exemplified in thepreparation of the 4,4'-diamino diphenylsulphope disodium formaldehydesulphoxylate, as follows:

12 grams of the-well known- 4,4'-diamino di phenylsulphone (see Frommand Wittmann, Be-

richte der Deutsch. Chem; Gesel1sch.'1908,-41, p. 2264) and 15 grams ofthe sodium formaldehyde sulphoxylate are dissolved in 35 ccm. of glacialacetic acid. Upon the addition of ether the resulting condensationproduct is precipitated; the

precipitate is washed with other, then with alcohol. After filteringoff, the precipitate is dissolved in water and neutralized with sodiumbicarbonate. By addition of alcohol and ether the product isprecipitated as a white powder which is dried in vacuum. It is readilysoluble in water and stable for some days in a slightly alkalinesolution.

Instead of working in glacial acetic solution. this compound may beprepared by addition of sodium formaldehyde sulphoxylate to the aqueoussolution of the dihydrochloride of the 4,4- diamino diphenylsulphone.The condensation product is isolated in the way described above.

By following the above method the disodium formaldehyde sulphoxylatederivatives of the other compounds mentioned may be prepared.

We claim as our invention:

1. As new chemicalcompounds, formaldehyde sulphoxylate derivatives ofthe general formula in which R is a radical selected from the groupconsisting of S, 5-8, SO and S02, and R is a radical selected from thegroup consisting of NH2, NH.CH2 S02 Na, and N02.

2. The method of preparing therapeutically active sulphoicylatederivative which consists in condensing with sodium formaldehydesulphoxylate in glacial acetic acid a compound of the general formula inwhich R is a radical from the group consisting of S, 8-8, SO, and S02,and R is a' radical from the group consisting of NH2, NH.CH2 S02 Na, and

N02, and recovering the resulting condensation product.

3. The method of preparing therapeutically active sulphoxylatederivatives which consists in 5 adding sodium formaldehyde sulphoxylateto an aqueous solution of the dihydrochloride of a compound of thegeneral formula in which R is a radical from the group consisting of S,8-8, SO, and S02, and R is a radical from the group consisting of NH2,NH.CHzSOzNa, and N01, and recovering the resulting condensation product.

4. The disodium formaldehyde sulphoxylate derivative of 4,4'-diaxninodiphenylsulphone.

5. The method of preparing 4,4'-diamino diphenylsulphone disodiumformaldehyde sulphoxylate which consists in condensing 4,4- diaminodiphenylsulphone with sodium formaldehyde sulphoxylate in glacial aceticacid, and re covering the resulting condensation product.

6. The method of preparing 4,4'-diamino diphenylsulphone disodiumformaldehyde sulphoxylate by adding sodium formaldehyde sulphoxylate toan aqueous solution of the dihydrochloride of 4,4'-diaminodiphenylsulphone, and recovering the resulting condensation product. 7.The sodium formaldehyde sulphoxylate derivative of4-amino-4-nitro-diphenylsuiphone.

8. The method oi preparing 4-amino-4'-nitro diphenylsulphone sodiumformaldehyde sulphoxylate which consists in condensing 4-ami'no-4'-nitro diphenylsulphone with sodium formaldehyde sulphoxylate in glacialacetic acid, and recovering the resulting condensation product.

9. The method of preparing 4-amino-4'-nitro diphenylsulphone sodiumformaldehyde sulph- 4 oxylate by adding sodium formaldehyde sulph- 13.The compound 4-amino-4'-nitro diphenyl-' o sulphoxide sodiumformaldehyde sulphoxylate.

14. The method of preparing 4-amino-4-nitro diphenylsulphoxide sodiumformaldehyde sulphoxylate which consists in condensing 4-amino-4'- nitrodiphenylsulphoxide with sodium formaldehyde sulphoxylate in glacialacetic acid, and recovering the resulting condensation product.

15. The method of preparing 4-amino-4' -nitro diphenylsulphoxide sodiumformaldehyde sulphoxylate by adding formaldehyde sulphoxylate to anaqueous solution of the dihydrochloride of 4- arnino-4'-nitrodiphenylsulphoxide, and recover. ing the resulting condensation product.

16. The compound 4,4-diamino diphenyl- 5 sulphide sodium formaldehydesulphoxylate.

17. The method of preparing lfl-diaminov diphenylsulphide disodiumformaldehyde sulphoxylate which consists in condensing 4,4'-diaminodiphenylsulphide with sodium formalde- 10 hyde sulphoxylate in glacialacetic acid, and recovering the resulting condensation product.

18. The method of preparing 4,4'-diamino diphenylsulphide disodiumformaldehyde sulphoxylate by adding formaldehyde sulphoxylate to 15anaqueous solution of the dihydrochloride of 4,4- diaminodiphenylsulphide, and recovering the resulting condensation product.

19. The compound 4-amino-4'-nitro diphenylsulphide sodium formaldehydesulphoxylate. 20 20. The method of preparing 4-amino-4'-nitrodiphenylsulphide sodium formaldehyde sulphoxylate which consists incondensing 4,4-amino 4'-nitro diphenylsulphide with sodium formaldehydesulphoxylate in glacial acetic acid, and re- 25 covering the resultingcondensation product.

'21. The method ofpreparing 4-amino-4'-nitro diphenylsulphide sodiumformaldehyde sulphoxylate by adding formaldehyde sulphoxylate to anaqueous solution of the dihydrochloride of 4- 30 amino-4'-nitrodiphenylsulphide, and recovering the resulting condensation product.

,22. The compound 4,4'-diamino diphenyldisulphide sodium formaldehydesulphoxylate.

23. The method of preparing 4,4'-diamino 35 diphenyldisulphide disodiumformaldehyde sulphoxylate which consists in condensing 4,4'-diaminodiphenyldisulphide with sodium formaldehyde sulphoxylate in glacialacetic acid, and recovering the resulting condensation product, 40

24. The method of preparing 4,4'-diamino diphenyldisulphide disodiumformaldehyde sulphoxylate by adding formaldehyde sulphoxylate to anaqueous solution of the dihydrochloride of 4,4'-diaminodiphenyldisulphide,- and recovering the resulting condensation product.

25. The compound 4-amino-4'-nitro diphenyldisulphide sodium formaldehydesulphoxylate.

26. The method of preparing 4-amino-4'-nitro diphenyldisulphide sodiumformaldehyde sulpho oxylate which consists in condensing 4-amino-4'-'nitro diphenyldisulphide with sodium formalde-.

"hyde sulphoxylate in glacial acetic acid, and recovering the resultingcondensation product.

27. The method of preparing 4-amino-4'-nitr o diphenyldisulphide sodiumformaldehyde sulphoxylate by adding formaldehyde sulphoxylate to anaqueous solution of the dihydrochloride of 4- amino-4'-nitrodiphenyldisulphide, and recover ing the resulting condensation product.6o

28. Compositions consisting of combination products of alkali metalformaldehyde sulphoxylate and one of the group consisting of diaminodiphenyl sulphide and diamino diphenyl sulphone.

SANFORD M. ROSENTHAL. HUGO BAUER.

- CERTIFICATE OF CORRECTION. Patent No 2,25LL,9s1. March 1 191mm SANFORDMO-ROSENTHAL, ET A1...

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction as follows: Page 2,sec ond column, line 25, cleim 20, for "L ih-amino read -lpemino-q andthat the said Letters Patent should be read with this correction thereinthat the same may conform to the record of the case in the PatentOfficeo Signed and sealed this 50th day of September, A. D, 19M

Henry Vern Arsdale, (Seal) 7 Acting, Commissioner of Patents.

